Cardiac fibrosis, a pathological consequence of cardiac injury, can be manifest either as localized scar or[unreadable] more diffuse interstitial fibrosis. The cells responsible for cardiac fibrosis are cardiac fibroblasts, which[unreadable] numerically are the most prevalent cells in the heart. Cardiac fibroblasts are regulated by hormones, many of[unreadable] which act via plasma membrane receptors, including ones that are linked to heterotrimeric G proteins and G-protein-[unreadable] regulated effectors. One such effector, adenylyl cyclase, catalyzes the formation of cyclic AMP from[unreadable] ATP and is the focus of this proposal. Cyclic AMP has anti-fibrotic actions that include inhibition of the[unreadable] transformation of "resting" cardiac fibroblasts to pro-fibrogenic myofibroblasts. This proposal will test several[unreadable] hypotheses related to the ability of increased cyclic AMP formation, produced by enhanced expression of[unreadable] adenylyl cyclase-6 (AC-6), to alter biochemical and functional activities of cardiac fibroblasts. Studies will be[unreadable] conducted using primary cultures of cardiac fibroblasts and, in addition, will involve the use of an animal[unreadable] model (angiotensin infusion in rats and mice) that produces cardiac fibrosis. The experiments focus on AC-6[unreadable] with an emphasis on its compartmentation with proximal and distal signaling components as well as impact[unreadable] of increased AC-6 expression on the fibrotic response, as assessed by several phenotypic characteristics.[unreadable] The results should provide proof-of-principle data regarding the potential for therapeutic targeting of cardiac[unreadable] fibroblasts by gene transfer with AC-6 and potentially other AC isoforms. It is likely that targeting of AC-6 to[unreadable] cardiac myocytes via intracoronary delivery of recombinant viral vectors (Project 1) will increase AC-6[unreadable] expression in fibroblasts. The general hypothesis of Project 2 is that increased expression of AC-6 in cardiac[unreadable] fibroblasts will alter the fibrotic response and favorably modify cardiac remodeling to improve cardiac[unreadable] function in the failing heart.